A human metabolic map of pharmacological perturbations reveals drug modes of action.

Understanding a small molecule's mode of action (MoA) is essential to guide the selection, optimization and clinical development of lead compounds. In this study, we used high-throughput non-targeted metabolomics to profile changes in 2,269 putative metabolites induced by 1,520 drugs in A549 lung cancer cells. Although only 26% of the drugs inhibited cell growth, 86% caused intracellular metabolic changes, which were largely conserved in two additional cancer cell lines.

Benefits of HIV-1 transmission cluster surveillance: a French retrospective observational study of the molecular and epidemiological co-evolution of recent circulating recombinant forms 94 and 132.

Introduction: Molecular surveillance is an important tool for detecting chains of transmission and controlling the HIV epidemic. This can also improve our knowledge of molecular and epidemiological factors for the optimization of prevention. Our objective was to illustrate this by studying the molecular and epidemiological evolution of the cluster including the new circulating recombinant form (CRF) 94_cpx of HIV-1, detected in 2017 and targeted by preventive actions in 2018.

Associations between common genetic variants and income provide insights about the socio-economic health gradient.

We conducted a genome-wide association study on income among individuals of European descent (N = 668,288) to investigate the relationship between socio-economic status and health disparities. We identified 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes (the Income Factor). Our polygenic index captures 1-5% of income variance, with only one fourth due to direct genetic effects.

Current insights into molecular mechanisms of environmental stress tolerance in Cyanobacteria.

The photoautotrophic nature of cyanobacteria, coupled with their fast growth and relative ease of genetic manipulation, makes these microorganisms very promising factories for the sustainable production of bio-products from atmospheric carbon dioxide. However, both in nature and in cultivation, cyanobacteria go through different abiotic stresses such as high light (HL) stress, heavy metal stress, nutrient limitation, heat stress, salt stress, oxidative stress, and alcohol stress. In recent years, significant improvement has been made in identifying the stress-responsive genes and the linked pathways in cyanobacteria and developing genome editing tools for their manipulation.

Biomolecular condensates in immune cell fate.

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins.

Extracellular vesicles in seminal plasma of Sahiwal cattle bulls carry a differential abundance of sperm fertility-associated proteins for augmenting the functional quality of low-fertile bull spermatozoa.

Poor male fertility significantly affects dairy production, primarily due to low conception rates (CR) in bulls, even when cows are inseminated with morphologically normal sperm. Seminal plasma is a key factor in evaluating the fertilizing ability of bull semen. The extracellular vesicles (EVs) in seminal plasma contain fertility-associated proteins like SPAM1, ADAM7, and SP10, which influence sperm function and fertilizing potential.

Functional innovation through new genes as a general evolutionary process.

In the past decade, our understanding of how new genes originate in diverse organisms has advanced substantially, and more than a dozen molecular mechanisms for generating initial gene structures were identified, in addition to gene duplication. These new genes have been found to integrate into and modify pre-existing gene networks primarily through mutation and selection, revealing new patterns and rules with stable origination rates across various organisms. This progress has challenged the prevailing belief that new proteins evolve from pre-existing genes, as new genes may arise de novo from noncoding DNA sequences in many organisms, with high rates observed in flowering plants.

An integrated approach to predict genetic risk for Mosquito-Borne diseases in the local Population of Tehsil Haripur, Khyber Pakhtunkhwa, Pakistan.

Highly variable response shown by individuals against mosquito-borne infections suggests that host genetic factors play an important role in determining mosquito-borne disease onset. Therefore, it is necessary to determine the genetic risk of these diseases in specific populations. The current study aimed to determine the percentage of individuals in the general population carrying mosquito-borne disease susceptibility and protection-related variants.

Rapid structural analysis of bacterial ribosomes in situ.

Rapid structural analysis of purified proteins and their complexes has become increasingly common thanks to key methodological advances in cryo-electron microscopy (cryo-EM) and associated data processing software packages. In contrast, analogous structural analysis in cells via cryo-electron tomography (cryo-ET) remains challenging due to critical technical bottlenecks, including low-throughput sample preparation and imaging, and laborious data processing methods. Here, we describe a rapid in situ cryo-ET sample preparation and data analysis workflow that results in the routine determination of sub-nm resolution ribosomal structures.

Association between changes in genital immune markers and vaginal microbiome transitions in bacterial vaginosis.

Bacterial vaginosis (BV), characterized by an imbalance in the vaginal microbiota, is a prevalent condition among women of reproductive age and a risk factor for human immunodeficiency virus, sexually transmitted infections, and preterm birth. BV is generally considered to induce mucosal inflammation, but the specific pathways and cell types involved are not well characterized. This prospective study aimed to assess associations between microbial changes and mucosal immune responses in BV patients.

Evaluation of ampicillin plus ceftobiprole combination therapy in treating Enterococcus faecalis infective endocarditis and bloodstream infection.

Enterococcus faecalis is responsible for numerous serious infections, and treatment options often include ampicillin combined with an aminoglycoside or dual beta-lactam therapy with ampicillin and a third-generation cephalosporin. The mechanism of dual beta-lactam therapy relies on the saturation of penicillin-binding proteins (PBPs). Ceftobiprole exhibits high affinity binding to nearly all E.

Stalled disomes marked by Hel2-dependent ubiquitin chains undergo Ubp2/Ubp3-mediated deubiquitination upon translational run-off.

Stalled ribosomes cause collisions, impair protein synthesis, and generate potentially harmful truncated polypeptides. Eukaryotic cells utilize the ribosome-associated quality control (RQC) and no-go mRNA decay (NGD) pathways to resolve these problems. In yeast, the E3 ubiquitin ligase Hel2 recognizes and polyubiquitinates disomes and trisomes at the 40S ribosomal protein Rps20/uS10, thereby priming ribosomes for further steps in the RQC/NGD pathways.

Convergent evolution of oxidized sugar metabolism in commensal and pathogenic microbes in the inflamed gut.

Inflammation-associated perturbations of the gut microbiome are well characterized, but poorly understood. Here, we demonstrate that disparate taxa recapitulate the metabolism of the oxidized sugars glucarate and galactarate, utilizing enzymatically divergent, yet functionally equivalent, gud/gar pathways. The divergent pathway in commensals includes a putative 5-KDG aldolase (GudL) and an uncharacterized ABC transporter (GarABC) that recapitulate the function of their non-homologous counterparts in pathogens.

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells.

Contact lenses for visual rehabilitation in post-keratoplasty eyes: A systematic review.

Purpose: To evaluate the role of contact lenses (CLs) in visual rehabilitation following keratoplasty.

Methods: Four databases, including PubMed, Scopus, Web of Science, and Embase were systematically searched for studies published between January 2010 and July 2023. Visual outcomes, daily wearing duration, subjective comfort, rate and etiology of CL discontinuation, corneal endothelial cell density, central corneal thickness, and complications were extracted.

Skeletal Editing through Cycloaddition and Subsequent Cycloreversion Reactions.

ConspectusSkeletal editing, which involves adding, deleting, or substituting single or multiple atoms within ring systems, has emerged as a transformative approach in modern synthetic chemistry. This innovative strategy addresses the ever-present demand for developing new drugs and advanced materials by enabling precise modifications of molecular frameworks without disrupting essential functional complexities. Ideally performed at late stages of synthesis, skeletal editing minimizes the need for the cost- and labor-intensive processes often associated with synthesis, thus accelerating the discovery and optimization of complex molecular architectures.

RNA recognition by minimal ProQ from Neisseria meningitidis.

Neisseria meningitidis minimal ProQ is a global RNA binding protein belonging to the family of FinO-domain proteins. The N. meningitidis ProQ consists only of the FinO domain accompanied by short N- and C-terminal extensions.

Mechanics of cell sheets: plectin as an integrator of cytoskeletal networks.

Epithelia are multicellular sheets that form barriers defining the internal and external environments. The constant stresses acting at this interface require that epithelial sheets are mechanically robust and provide a selective barrier to the hostile exterior. These properties are mediated by cellular junctions which are physically linked with heavily crosslinked cytoskeletal networks.

Metallofullerenol Gd@C(OH) preserves human erythrocyte plasma membrane integrity from AAPH-induced oxidative stress: molecular mechanisms and antioxidant activity.

Metallofullerenols and fullerenols have attracted attention due to their remarkable ability to interact with various biologically relevant molecules, paving the way for biomedical applications, ranging from medical imaging techniques to drug carriers, acting with increased efficiency and reduced side effects. In this work, we investigated the effects of two fullerene derivatives, Gd@C(OH) and C(OH), on erythrocyte membrane components under oxidative stress conditions induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) as a source of peroxyl radicals. The results demonstrated that gadolinium encapsulation within the fullerene cage enhanced the electron affinity of Gd@C(OH), resulting in stronger antioxidant activity.

Modulation of Protein-Protein Interactions with Molecular Glues in a Synthetic Condensate Platform.

Misregulation of protein-protein interactions (PPIs) underlies many diseases; hence, molecules that stabilize PPIs, known as molecular glues, are promising drug candidates. Identification of novel molecular glues is highly challenging among others because classical biochemical assays in dilute aqueous conditions have limitations for evaluating weak PPIs and their stabilization by molecular glues. This hampers the systematic discovery and evaluation of molecular glues.

Chromosome-scale genome assembly reveals how repeat elements shape non-coding RNA landscapes active during newt limb regeneration.

Newts have large genomes harboring many repeat elements. How these elements shape the genome and relate to newts' unique regeneration ability remains unknown. We present here the chromosome-scale assembly of the 20.

Analysis of TEM micrographs with deep learning reveals APOE genotype-specific associations between HDL particle diameter and Alzheimer's dementia.

High-density lipoprotein (HDL) particle diameter distribution is informative in the diagnosis of many conditions, including Alzheimer's disease (AD). However, obtaining an accurate HDL size measurement is challenging. We demonstrated the utility of measuring the diameter of more than 1,800,000 HDL particles with the deep learning model YOLOv7 (you only look once) from micrographs of 183 HDL samples, including patients with dementia or normal cognition (controls).